A new progesterone receptor modulator, CDB-29 14, with potent antiovulatory properties will be investigated for its potential as a contraceptive for women when delivered through a sustained-released system such as a contraceptive vaginal ring. The molecule has been synthesized and developed by the National Institute of Child Health and Human Development (NICHD) for emergency contraception. Toxicology studies conducted at the NICHD indicate that the compound is safe, and the Food and Drug Administration (FDA) has approved an Investigational New Drug for clinical study. CDB-2914 binds to the progesterone receptor (PR) with high affinity and is a potent progesterone antgonist (PA). It exhibits potent antiovulatory properties in animal models. These properties of CDB-2914 make it attractive as a potential contraceptive, and preliminary studies suggest the possibility of delivering CDB-2914 continuously at low doses via a silastic vaginal ring. The research project described in this proposal will include the following studies: 1) The mechanism of action at the ovarian level will be explored. 2) CDB-2914 will be formulated into vaginal gel and rings and will involve assessment of in vitro release and stability studies. The extensive experience of The Population Council in laboratory scale manufacture of contraceptive rings (CRs) and in evaluation of their clinical performance provides a firm base for completing the development of the CDB-2914 device. 3) A radioimmunoassay will be set up for CDB-2914 and validated for kinetic studies to be conducted in animals and in women. 4) The potential proliferative action of CDB-2914 on human breast cells will be investigated as well for safety purposes, in anticipation of eventual long-term contraceptive efficacy studies in women. Parallel studies in women and monkeys, which relate to the above studies but for which funding has been obtained or will be requested from other sources, will be described separately. Ultimately, this new estrogen-free method should be associated with fewer side effects than estrogen-containing contraceptives and will likely induce endometrial changes resulting in amenorrhea, a condition highly acceptable to women.